PROJECT SUMMARY/ABSTRACT A state-of-the-art ultra-performance liquid chromatography (UPLC) system, equipped with radiation, UV absorbance, and MS detectors is requested. The instrument will be available specifically for the analysis of short- lived radioactive samples at UCLA, as the nature of these samples prevents users from accessing most instruments on campus. The instrument will be a vital component to support the aims of a broad range of NIH- funded projects. These projects involve the development of new technology platforms for synthesizing PET tracers, new radiochemistry methods to create previously-inaccessible labeled molecules, new prosthetic groups for multi-modality labeling of biomolecules (e.g. peptides, proteins, etc.), the development and evaluation of novel PET tracers to enable in vivo imaging of novel biological targets, the development and use of high- throughput screening methods to discover new PET tracers, and the use of PET tracers to discover metabolic targets and study the role of metabolism in cancer and other diseases. All of these projects require rapid analysis of radioactive samples to determine reaction yield, identity and quantity of side products, assess chemical and radiochemical purity, or identify radio-metabolites arising from biochemical reactions in vivo. The proposed radio- UPLC-MS system will be supported and administered by the Crump Cyclotron and Radiochemistry Technology Center, a facility formed to enhance the accessibility of radiochemistry infrastructure, equipment, methods, and applications (e.g. supplying PET tracers, performing in vivo radio-metabolite analysis) to the broader community. Although two high-performance liquid chromatography systems equipped with radiation detectors (radio-HPLC) are available for measuring radioactive samples, the instruments are fully utilized and fall far short of meeting the needs of the user group and the Major Projects. This limitation arises primarily from the low-throughput nature of existing instruments. Due to the long analysis time needed for each sample, combined with the limited working time (due to the short half-life of samples, e.g. 110 min if labeled with fluorine-18), it is only practical to run one user?s experiment (with up to 6-12 samples/day) on each instrument per day. This severely limits the depth of experiments that can be performed or forces many experiments to be carried out over multiple days, increasing their cost and timeframe (since the radionuclide and relevant radiotracer(s) must be re-synthesized each day). Furthermore, experiments cannot be performed with the frequency that users require. The proposed radio-UPLC-MS system will address these issues. Reduction of separation times compared to radio-UPLC (e.g. 1 min vs 30 min in one demonstration), and the integration of an autosampler, will greatly increase the number of samples that can be analyzed per day, ensuring that the Major and Minor Users, as well as researchers across campus using core PET/CT and radiochemistry services, have the needed resources to complete their projects. The increased throughput will also improve research, by increasing the depth of studies (more data points) and number of replicates, and will also enable new types of high-throughput experiments.